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Sunday, 29 April 2018

Know your NUCLEOTIDES - by Dr Peter Köppel and Rachel Hoyle

In this week's blog Dr Peter Köppel and Rachel
Hoyle investigate the
importance of nucleotide
nutrition in relation to the gut...

In Japan, infant formula has been
supplemented with nucleotides
since 1965, but it took the rest of
the world another 20 to 30 years
to catch onto the concept.
Supplementation of infant
formula is reported to have
beneficial effects on faecal microbiota,
by increasing the count of ‘friendly’
bifidobacteria1, decreasing the count of
enterobacteria, reducing the incidence
of diarrhoea2
and modulating immune
function3. Yet, the proportion of the population
which understands the importance of
dietary nucleotides – and that includes
those in healthcare professions as
well – is miniscule; nearly everyone
with an interest in health understands
the importance of macronutrients,
including proteins and their composite
amino acids, fats (along with healthy
essential fatty acids) and carbohydrates
(especially complex ones from
plant-source foods). In terms of
micronutrients, we’re all familiar with
vitamins and minerals and more are
becoming aware of the vital role played
by plant compounds (phytonutrients)
that act as anti-inflammatory agents,
antioxidants (free radical scavengers)
and also help modulate a wide range
of key metabolic processes in all our
body systems (for example, endocrine,
immune, cardiovascular, musculoskeletal,
brain/nervous system, dermis
[skin, hair, nails]).
But who’s ready to accept another,
whole category of nutrient, namely
nucleotides? We believe any person
who’s spent time digesting (pun
intended) the science around these
nutrients will be convinced. And it’s
why we feel it’s so important to get the
word out far and wide.
This has triggered research by us
into whether nucleotides are important
in adult health and if supplemental
nucleotides can enhance health or
prevent or treat clinical conditions.

What are nucleotides?

DNA is the blueprint of life and
nucleotides are the building blocks of
the double helix. Nucleotides consist
of a nitrogen-containing base (mostly
adenine, thymine, cytosine, guanine
and uracil), a five-carbon sugar (ribose
or deoxyribose) and one to three
phosphate groups.
FUNCTIONS
Obviously, nucleotides are an integral
part of the structure of DNA and RNA
and are essential compounds in the
energy transfer system (i.e. in ATP,
NADP, NADH)4, 5, thus it has been
assumed that they play an important
role in carbohydrate, lipid, protein and nucleic acid metabolism3,6.
It is anticipated that cells of tissues
which are growing rapidly or have a
high turnover rate will have a higher
requirement for nucleotides, for DNA/RNA
synthesis, than cells of tissues growing
more slowly. Such cells include enterocytes
in the gastrointestinal tract and cells of the
immune system4.

The source of nucleotides

Nucleotides can be synthesised by the body
de novo from some amino acids, for example,
glutamine, aspartate, glycine and formate6.
Nucleotides, nucleosides, nucleic acids, bases
and deoxyribose can also be salvaged from
DNA and RNA degradation or from the diet
and be recycled6.
It appears that the intestinal mucosa,
bone marrow haematopoietic cells and
lymphoid tissue have a limited capacity for
de novo synthesis and probably depend
more heavily on the salvage pathways that
supply nucleotides from the diet or from the
degradation of DNA and RNA3,7. Thus, if the
exogenous supply of nucleotides is low, these
tissues may struggle to fulfil their need for
nucleotides.

Dietary nucleotide metabolism

Nucleotides are a normal component of
the adult human diet and are ingested in
the form of nucleoproteins5. Proteases and
nucleases degrade nucleoproteins and
nucleic acids into nucleotides; phosphatases
and nucleotidases cleave the phosphate
group(s) to yield nucleosides.
Dietary nucleotides are not considered
essential in the traditional sense because
they can be synthesised by the body7.
However, a number of investigators
have described dietary nucleotides as
conditionally essential in a variety of clinical
situations and during development7,8.
But it’s the intestinal tract that has the
highest rate of cellular turnover in the
body, this rate being greater during periods
of infection or when the gut mucosa has
been damaged and is in need of repair.
Additionally, the 100 trillion or so microbes
that make up the gut’s microbiome turn over
even more rapidly, and have an insatiable
requirement for nucleotides to build RNA
and DNA within the nucleus of every new
cell. There is approximately 1,000 times
more RNA in a typical cell than DNA, most
of it present as messenger (mRNA), transfer
(tRNA) and ribosomal (rRNA) RNA, with
the all-important mRNA comprising usually
around just one to five per cent of total
cellular RNA.
The slides below show the cross-section
of the gut, and how under ‘stress’ the villi
development of an animal becomes stunted
and lesions start to form. Just three weeks
of nucleotide supplementation enabled
the villi to grow to optimal levels (25 per
cent higher), and there was improved
morphology and surface area available for
nutrient absorption9.
Histological slides from Burrells et al.

Are dietary nucleotides essential?

Dietary nucleotides could theoretically
become conditionally essential under three
circumstances10:

During periods of insufficient intake.

Where there is a high demand/high rate
of growth, and

In the presence of disease3

It has been demonstrated that
enterocytes, whilst having a high demand
for nucleotides, have a low capacity for
de novo synthesis8. Thus, it could be
postulated that enterocytes rely more
heavily on an exogenous supply of
nucleotides from the diet. Further, if the
dietary intake of nucleotides is low, due to
a restrictive diet, these compounds could
be considered conditionally essential.
In a study examining the effect of a
nucleotide supplement on symptoms
in Irritable Bowel Syndrome, it was felt
that dietary nucleotides were probably
not essential in healthy people but under
conditions of stress, illness or a poor
diet nucleotides may well become semiessential11.

The evidence for essentiality – do diets devoid of nucleotides cause problems?

The supplementation of infant formula
with nucleotides is considered beneficial
since it has been found to influence lipid
metabolism, immunity and tissue growth,
development and repair12. The majority
of standard infant formulas are now
supplemented with nucleotides.
Studies have demonstrated that
babies fed nucleotide-supplemented
infant formula have increased ‘friendly’
bifidobacteria counts in faeces compared
to infants fed standard formula milk, but
counts were still lower than found in
breastfed babies13.
Nucleotide supplemented formulas
have also decreased the prevalence and
duration of diarrhoeal disease in infants
but this was not associated with changes
in faecal microflora14. Thus, mechanisms
other than the modification of faecal
microflora, for example, effects on the
immune system, might be responsible for
the reduction in diarrhoeal disease.
Infant studies also suggest those
receiving nucleotide supplemented
formula have an improved antibody
response following immunisation15,16.
Feeding a nucleotide supplemented
diet to rats has also demonstrated
gastrointestinal benefits. Rats with
experimentally induced ulcerative ileitis
fed nucleotide-supplemented enteral and
parenteral feeds show accelerated healing
of small-bowel ulcers compared with
rats fed a standard formula14. In another
study, weanling rats fed a nucleoside supplemented
diet saw increased villus
height and enhanced gut maturation
compared to rats fed a standard diet17.

Dietary nucleotides and deficiencies: where do dietary nucleotides come from?

The short answer is, from a lot of foods
that most of us eat very little of these
days. The richest sources are offal meats,
yeast extracts and fermented foods,
such as traditionally fermented tofu,
tempeh and natto (Fig. 2, below). Most
plant foods contain very low levels of
nucleotides (Fig. 2), with broccoli being
an exception.

Nucleotide supplementation

A number of studies examining the
effects of supplemental nucleotides
have also been carried out in differing
populations and for different beneficial
effects.
Treatment by dietary nucleotides* has
been shown to be beneficial for people
with IBS. *Using a nucleotide supplement
containing a balanced formula of
pyrimidine and purine nucleotides11.
A total of 37 people with IBS
found that taking a nucleotide-based
supplement (one 500mg capsule three
times daily) resulted in a statistically
significant improvement in three of
seven symptom scores of IBS compared
to placebo11. Namely, abdominal pain,
urgency and a feeling of incomplete
evacuation. Severity of diarrhoea was
also improved. The improvements
were modest, as would be expected in a
community sample (i.e. not drawn from a
clinical trial population), but no adverse
side effects were reported.
The authors speculate that improved
gut function could be via similar
mechanisms found in animal studies,
namely increased mucosal protein, DNA
and villus height.

Conclusion

It is clear that nucleotides are involved
in many aspects of cellular metabolism,
growth and immune function. Their precise
mechanism of action remains to be fully
understood.
The addition of nucleotides to infant
formula milk and more recently to enteral
food clearly demonstrates a consensus in
the scientific community that nucleotides
are essential for normal functioning of the
body.
It is accepted that dietary nucleotides are
conditionally essential under conditions
of immunological stress, during periods
of rapid growth or insufficient intake and
for disease or injury to the gastrointestinal
tract. Much of this research has been
carried out in animals, but there are
encouraging results from human trials
of enteral food, and the independent
clinical studies with IBS11, URTI (colds)
infections18, stress (intensive19, moderate
endurance20 and resistance21).
The more we understand about the
roles nucleotides play – particularly in
areas of the body with rapid cellular
turnover rates, most notably the gut
mucosa, the gut microbiome and the
immune system – the more we realise that
nucleotides may not just be ‘conditionally
essential’, but essential for most of us, most
of the time. Our high stress levels, including
exercise-induced stress, along with our
ever-decreasing nucleotide intake from
food sources in the Western diet, and
even trauma and injury, will all contribute
to dramatically increasing our dietary
requirement for these nutrients. For references, please visit
www.ihcan-mag.com/References

About the authors

Dr Peter Köppel has a
PhD in Biochemistry
and Immunology.
He was trained in
Biochemistry, with
a special interest in
clinical immunology, at the
Institute of Virology at the University of
Zürich. He then worked as a researcher
in osteoarthritis and osteoporosis in
a pharmaceutical company in Basel.
As Managing Director of Chemoforma
and Pro Bio, in Switzerland, Dr Köppel
has, for over 20 years, led research
and production of special nucleotide
ingredients for both animal and human
nutrition. This has led him to being
seen as one of the world’s foremost
experts on nucleotides for health and
performance.Rachel Hoyle, BSc,
a science graduate,
has been involved in
the development of
special nucleotidebased
products, in
collaboration with Dr Peter
Köppel, since the 1990s. Her initial
responsibility was to develop natural
products that reduce the dependency
on antibiotics in animal nutrition. More
recently, Rachel has devoted her time
to the research and development of
nucleotide supplements for human
health. Her company, Nucleotide
Nutrition, now markets these products,
which are all based on the Nutri-tide
formula.

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